Rare genetic diseases impact over 400 million patients globally, yet diagnostic and therapeutic unmet needs persist. This thesis analyzed whole genome sequencing data from 235 ataxia-telangiectasia (A-T) patients to enhance genetic diagnosis and systematically assess possibilities for antisense oligonucleotide (ASO) therapies targeting RNA mis-splicing. With an augmented bioinformatics pipeline, 98.7% of A-T patients received a complete genetic diagnosis. Additionally, 15% (35/235) of patients were identified to have at least one ASO-amenable variant. Follow-up experiments confirmed the mis-splicing events and ASO-amenability predicted with computational tools. Advanced ASO development for a prioritized mis-splicing variant in ATM gene enabled launch of an individualized clinical trial to evaluate impact on disease progression. Analysis of two ABCA4-associated retinopathy cohorts revealed consistency in estimated ASO-amenability rates, suggesting potential broader applicability to other rare diseases. Overall this methodology transforms traditional notions of therapy development for ultra-rare diseases. By systematically pinpointing pathogenic variants in rare disease patients and designing variant-targeting ASOs to correct RNA mis-splicing events, rapid translation of personalized medicines based on characteristics of pathogenic variants is made possible. Study innovations in genetic diagnosis, assessment of therapeutic potential, and demonstration of clinical feasibility provide a framework for translating personalized medicine to rare disease patients. Expansion to additional cohorts and diseases along with refinements in analysis algorithms will further meet diagnostic and therapeutic unmet needs in rare diseases.
희귀 유전성 질환은 전 세계적으로 수백만명에 영향을 미치지만, 진단 및 치료의 한계가 여전히 존재한다. 본 학위논문에서는 235명의 모세혈관 확장성 운동실조증 환자들의 전장유전체 염기서열을 분석하여 유전학적 진단을 개선하고 유전변이로 인한 RNA 미스스플라이싱 (mis-splicing)을 표적으로 하는 안티센스올리고뉴클레오티드 (antisense oligonucleotide) 적용 가능성을 체계적으로 평가하였다. 생물정보학적 알고리즘을 사용한 유전변이 분석 방법을 통해 99%의 환자에서 질병유발 변이들을 밝혔으며, 9-15%의 환자들이 안티센스올리고뉴클레오티드로 교정 가능한 변이를 갖고 있는 것으로 분류되었고, 실험적 방법을 통해 검증되었다. 이러한 유전체 분석 방법론은 RNA 미스스플라이싱 결함을 교정하기 위한 유전변이 특이적 안티센스올리고뉴클레오티드를 이용한 개인 맞춤형 치료제 개발을 가능하게 한다.
